7. Project Summary/Abstract The overall goal of this application is to elucidate the function of transmembrane 6 superfamily member 2 (TM6SF2), a protein of unknown function associated with non-alcoholic fatty liver disease (NAFLD). This goal is highly congruent with the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which supports ongoing efforts to elucidate the pathogenesis of NAFLD with a view to early detection, intervention, and prevention of chronic progressive liver disease. To identify genes that contribute to NAFLD, the Hobbs/Cohen laboratory performed an exome-wide association study for liver fat content. This screen revealed that a common variant (E167K) in TM6SF2 was associated with increased hepatic fat content and leads to progression of NAFLD to cirrhosis. The project proposed here will take advantage of the trainee?s expertise in lipid mass spectrometry to identify unique changes in lipid biochemistry in Tm6sf2 knockout mice. The Specific Aims are: Aim 1: Determine effects of TM6SF2 inactivation on hepatic and circulating lipid composition in mice. Aim 2: Establish a cell-based assay to determine the biochemical function of TM6SF2. The project will provide the basis of a multi-faceted research training program that will expand the trainee?s current knowledge of lipid biochemistry in the context of NAFLD, and provide additional training in protein-lipid biochemistry and human molecular genetics. In addition to laboratory training, the program will broaden the trainee?s knowledge of liver disease and pharmacological treatment strategies through course work, laboratory meetings and journal clubs, departmental/university lectures, and national conferences. By combining her analytical expertise in lipid mass spectrometry with biochemistry/molecular biology skills and biomedical perspective, this program will leave the trainee well-positioned to pursue a career in the biomedical sciences.